CZ283081B6 - Imidazopyridine derivatives, process of their preparation and pharmaceutical preparations in which they are comprised - Google Patents

Abstract

Imidazopyridine Derivatives of Formula I wherein R is as defined below and R 1 is R 1, R 2, R 2, R 3, R 4, R 4, X and Y are as defined herein and their salts, which exhibit angiotensin II-antagonistic properties and can therefore be used to treat hypertension, aldosteronism, cardiac insufficiency and increased intraocular pressure, as well as central nervous system disorders.

Description

The invention relates to imidazopyridine derivatives, a process for their preparation and pharmaceutical preparations based thereon.

BACKGROUND OF THE INVENTION

Similar compounds are known from EP-A2-0400 974 and EP 0 505 893.

SUMMARY OF THE INVENTION It was an object of the present invention to provide novel compounds having valuable properties which can be used in particular for the manufacture of medicaments.

SUMMARY OF THE INVENTION

The present invention provides imidazopyridine derivatives of formula (I)

(I) where

R is a radical of formula

R ¹ is A or cyclopropyl

R ² represents cyano or ΙΗ 5-tetrazolyl,

R ³ is C 2 -C 6 alkenyl which is once substituted with Ar, or -CH ₂ -R ⁹ or -CHR ¹⁰ Ar,

R ⁶ and R ⁷ are each hydrogen, A, Ar or ArCH ₂ -, or

R ⁶ and R ⁷ taken together represent an alkylene chain of 4 to 5 carbon atoms optionally substituted once with -CO-N (A) ₂ and / or -NH-CO-A and / or interrupted by an oxygen atom or -NR ¹⁶ -,

- 1 GB 283081 B6

R ⁹ is -C (= N-OA) -A, Het 1, -CO-NR ⁶ R ⁷ or -S (O) _m -Ar,

R ¹⁰ represents a carboxy group or a group of formula COOA,

R ¹⁶ represents a group of formula Ar, COOA or SO 2 -Ar,

A is C 1 -C 6 alkyl,

Ar is unsubstituted phenyl or phenyl substituted once with A, OA, COOA, NO ₂ or Hal,

Het ¹ is 2-oxo-3-Ar-5-oxazolidinyl,

Hal represents a fluorine, chlorine, bromine or iodine atom and m represents 0, 1 or 2 as well as their salts.

It has now been found that the compounds of the formula I and their salts have very valuable pharmacological properties with good tolerability. In particular, they have angiotensin II antagonistic properties and can therefore be used as active substances of medicaments for the prophylaxis and / or therapy of heart diseases, blood circulation and vascular diseases, in particular for the treatment of angiotensin II-dependent hypertension, aldosteronism, cardiac insufficiency and elevated intraocular pressure, as well as disorders of the central nervous system, as well as vascular and heart hypertrophy and hyperplasia, angina pectoris, heart attack, stroke, restenosis after angioplasty. Furthermore, they can be used in by-pass operations and for the prophylaxis and / or therapy of arteriosclerosis, glaucoma, macular degeneration, hyperuricaemia, renal impairment such as renal failure, Nephropathia diabetica, Rethinopathia diabetica, Psoriasis, angiotensin-mediated female reproductive organ disorders II, perception disorders such as dementia, amnesia, memory function disorders, anxiety disorders, depression and / or epilepsy.

These effects can be determined by conventional in vitro or in vivo methods such as those described in US Patent Nos. 4,880,804 and 5,036,048 and PCT Application WO 91/14367, as well as in AT Chiu et al., J. Pharmacol. . Exp. Therap. 250, 867-874 (1989) and P. C. Wong et al., Ibid. 252, 719-725 (1990; in vivo, in rats).

The invention also relates to a process for the preparation of imidazopyridine derivatives of the formula I and their salts, which comprises:

a) a compound of formula II

E — CH · (Π), where it represents a chlorine, bromine or iodine atom, or a free or reactive functionally modified hydroxy group, and

-2GB 283081 B6

R ² has the abovementioned meanings, is reacted with a compound of formula III

H-R (III), wherein R is as defined above, or is

b) a compound of formula IV

(IV), where

R ¹⁷ represents a group of the formula R'-CO or hydrogen, and

R ¹⁸ represents a hydrogen atom when R ¹⁷ represents a group of the formula R'-CO, or a group of formula R * -CO if R ¹⁷ represents a hydrogen atom, and

R ¹ , R ² and R ³ are as defined above, heated in polyphosphoric acid, acetic acid or diglyme to a temperature in the range of 80 to

Or 180 ° C

c) a compound of formula VII

(VIII),

-3GB 283081 B6 where

R ¹ and R ² are as defined above, is reacted with a compound of formula VIII

ER ³ (VIII), where

R ³ and E are as defined above, or are

d) for the preparation of a compound in which R ³ represents a group of the formula CH 2 -CO-NR ⁶ R ⁷ , a carboxylic acid corresponding to the general formula I is reacted but instead of a radical R ³ contains a group of the formula -CH 2 -COOH or one of its functional derivatives , with a compound of the formula HNR ⁶ R ⁷ , or with

e) a compound of formula I is freed from one of its functional derivatives by treatment with a solvolyzing or hydrogenolyzing agent, and / or in a compound of formula Ijeden or more radicals R and / or R ² is converted to one or more other radicals R and / or R ² and or the base or acid of the formula I is converted into one of its salts.

In the above formulas, the residue A preferably represents methyl, furthermore ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, furthermore also pentyl, 1-, 2- or 3-methylbutyl, 1,1-, l- , 2- or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl, 1,1-, 1,21,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1,2- or 1,2,2-trimethylpropyl or cyclopropyl.

Hal preferably represents fluorine, chlorine or bromine, but may also represent iodine.

R represents a residue derived from 3H-imidazo [4,5-c] pyridine (3H-IP), more specifically

2-R'-4- (thi) oxo-5-R ³ -6-R ⁴ -4,5-dihydro-3 H -imidazo [4,5- c] pyridin-3-yl residue.

Ar preferably represents n phenyl, o-, m- or p-tolyl, o-, m- or p-ethylphenyl, o-, m- or p-methoxyphenyl, o, m- or p-ethoxyphenyl, o-, m- or p -carboxyphenyl, o-, m- or p-methoxycarbonylphenyl, o-, m- or p-ethoxycarbonylphenyl, o-, m- or p-nitrophenyl, o-, m- or p-fluorophenyl, o-, m- or p-chlorophenyl or o-, m- or p-bromophenyl.

The radical R @ ¹ preferably has a straight chain and preferably represents A, in particular ethyl, propyl or butyl, furthermore methyl, pentyl or hexyl, as well as cyclopropyl.

The radicals R ² is preferably ΙΗ-5-tetrazolyl.

The radical R ³ is preferably -CH 2 -CO-NR ⁶ R ⁷ . Further preferred meanings of the radical include Ar-alkenyl (C 2 -C 6 alkenyl, e.g. cinnamyl α-CH 2 C (= NOA) -A], e.g. 2-methoxyimino-3,3-dimethyl-butyl).

The radicals R ⁵ and R ⁶ preferably contain 1, 2 or 3 carbon atoms and are preferably methyl and ethyl.

The compounds of formula (I) may contain one or more chiral centers and, therefore, may be present

-4E 283081 B6 occur in various optically active or optically inactive forms. Formula I includes all these forms.

The compounds of the formula and the starting materials for their preparation are generally prepared by methods known to the person described in the literature (for example, in standard publications such as Houben-Weil, Methoden der Organischen Chemie, Georg-Thieme Verlag, Stuttgart; A2-0 430 709 and in U.S. Pat. No. 4,880,804) under conditions which are known and suitable for carrying out said reactions. It is also possible to use methods known per se, not mentioned here in greater detail.

If desired, the starting materials can also be prepared in situ, so that they are not isolated from the reaction mixture, but are further reacted directly to the compounds of formula I.

The compounds of formula I can preferably be obtained by reacting compounds of formula II with compounds of formula III. In particular, biphenyl derivatives of the formula I (in which X is absent) are readily available in this way.

In the compounds of formula II, E is preferably chlorine, bromine, iodine or a reactive functionally modified hydroxy group such as, for example, C1-6 alkylsulfonyloxy (preferably methylsulfonyloxy) or C6-10 arylsulfonyloxy (preferably phenyl or p-tolylsulfonyloxy) .

The reaction of a compound of formula II with a compound of formula III is conveniently carried out by first converting the compound of formula II with a base, for example using an alkali metal alkoxide such as sodium methoxide or potassium tert-butoxide in an alcohol such as methanol or tert-butanol, or using an alkali metal hydride such as sodium hydride or an alkali metal alkoxide in dimethylformamide (DMF). This salt is then reacted in an inert solvent, for example an amide, such as DMF, N-methylpyrrolidone or dimethylacetamide or a sulfoxide, such as dimethylsulfoxide (DMSO), suitably at a temperature of from -20 to 100, preferably from 10 to 30 ° C. Also suitable as bases are alkali metal bicarbonates such as sodium or potassium bicarbonate.

Further, compounds of formula I may be obtained by cyclization of compounds of formula IV. The cyclization is conveniently carried out by heating with polyphosphoric acid, acetic acid or diglyme to a temperature of from about 80 to about 180, preferably from about 120 to about 160 ° C.

Compounds of formula I can also be obtained by reacting a compound of formula VII (Formula VII corresponds to formula I but with H in place of ^R3) with a compound of formula VIII. The reaction is preferably carried out in an inert solvent, for example an acid amide such as DMF, N-methylpyrrolidone, 1,3-dimethyl-2-oxohexahydropyrimidine or hexamethylphosphoric triamide, an alcohol such as methanol or tert-butanol, an ether such as THF, or a halogenated hydrocarbon such as dichloromethane or mixtures thereof and / or in the presence of an alkali metal alkoxide such as sodium methoxide or potassium tert-butoxide, an alkali metal hydride such as sodium hydride or potassium hydride, an alkali metal carbonate such as sodium carbonate or potassium carbonate, an alkali metal bicarbonate such as sodium or potassium bicarbonate, or a tertiary amine such as triethylamine or ethyldiisopropylamine at a temperature in the range of about -30 to 200, preferably from 20 to 60 ° C.

Compounds of formula I which contain a group of formula -C (= NR ¹²⁾ -, can be prepared from carbonyl compounds which, instead of this group contain a carbonyl group -CO- but otherwise correspond to the formula I, reacting a compound of formula H2N- R ¹² . The latter includes ammonia, hydroxylamine, O-alkyl-, Ο-alkenyl-, O-alkynyl- and Oarylhydroxylamines, cyanamide and primary amines of the formula R ¹³ -NH ₂ .

-5GB 283081 B6

Compounds of formula I wherein R ³ is a group of formula CH 2 -CO-NR ⁶ R ⁷ may be prepared by reacting a carboxylic acid corresponding to formula I, but containing a group of formula -CH 2 -COOH instead of the radical R ³ or a functional derivative thereof with a compound of the formula HNR ⁶ R ⁷ . This is expediently carried out by conventional methods of peptide synthesis, for example as described in Houben-Weyl, 1c, Volume 15/11, pp. 1-806 (1974).

The reaction is preferably carried out in the presence of a dehydrating agent, for example a carbodiimide such as Ν, Ν'-dicyclohexylcarbodiimide (DCCI), Ι, Γ-carbonyldiimidazole or N-3-dimethylaminopropyl-N'-ethylcarbodiimide (DAPECI), propanephosphonic anhydride (cf. Chem., 92, 129 (1980), diphenylphosphoryl azide or 2-ethoxy-N-ethoxycarbonyl-1,2-dihydroquinoline, in an inert solvent, for example a halogenated hydrocarbon such as dichloromethane, an ether such as THF or dioxane, an amide such as is DMF or dimethylacetamide, a nitrile, such as acetonitrile, at a temperature in the range of about -10 to 40 ° C, preferably about 0 to about 30 ° C.

Instead of carboxylic acids, suitable reactive derivatives of these substances, for example those in which the reactive groups are intermediately protected by protecting groups, can also be used for the reaction. For example, the acids can be used in the form of their reactive esters, which can conveniently be formed in situ, for example by adding 1-hydroxybenzotriazole or N-hydroxysuccinimide.

Further, the compounds of formula (I) may be obtained by solvolytic (e.g. hydrolytic) or hydrogenolytic release from their functional derivatives.

Further, it is possible to produce a compound of the formula I by some of the above methods, but contains a functionally modified (protecting group) 1H-(or 2H) -5-tetrazolyl group at the 5-tetrazolyl group at the 1-position (or the 2-position). Suitable protecting groups are, for example, triphenylmethyl which is cleavable with hydrochloric or formic acid in an inert solvent or solvent mixture, for example a mixture of ether, dichloromethane and methanol; 2-cyanoethyl which is cleavable by sodium hydroxide in a mixture of water and tetrahydrofuran; and a nitrobenzyl group that is cleavable by hydrogen in the presence of Raney nickel in ethanol (cf. EP-A2-0 291 969).

Some of the starting materials, in particular those of the formulas II and VIII, are known. If they are not known, they can be prepared by methods known per se, analogously to known substances. For example, compounds of formula III are available by reaction of carboxylic acids of formula R'COOH with compounds of formula IX

(IX) in the presence of polyphosphoric acid. In this case, the group E (preferably chlorine) is hydrolyzed to first produce compounds of the formula III, but where R ³ is hydrogen, which can then be reacted with compounds of the formula VIII.

For example, compounds of formula IV can be obtained by reacting a compound of formula X

-6GB 283081 B6

(X) in which the amino group is protected by an amino protecting group (for example benzyl, AO-CO- or benzyloxycarbonyl) with a compound of formula II, followed by cleavage of the protecting group and reaction with an acid of formula R'-COOH, or its functional derivative. These compounds are generally not isolated but formed in situ in the latter reaction.

For example, compounds of formula VII are available by reacting compounds of formula III but bearing a hydrogen atom instead of the radical R ³ with compounds of formula II.

The compounds of formula I is also possible to convert into other compounds of formula Itak that one or more of the radicals R and / or R @ ² to other radicals R and / or R ^2nd For example, by hydrogenation on Raney nickel or palladium on carbon in an inert solvent such as methanol or ethanol, the nitro group can be reduced to the amino group and / or the free amino and / or hydroxy groups can be functionally changed and / or from the functionally changed amino group and / or the hydroxy groups may be liberated by solvolysis or hydrogenolysis and / or the nitrile groups may be converted to carboxy groups or reacted with a nitrogen acid derivative such as sodium azide in N-methylpyrrolidone or trimethyltin azide in toluene to form tetrazolyl groups and / or the thioether groups may be oxidized to groups of SO- or SO ₂ -, for example with hydrogen peroxide or with a peracid such as 3-chloroperbenzoic acid.

Thus, for example, the free amino acids may be acylated in the usual manner with an acid chloride or acid anhydride, or alkylated with an unsubstituted or substituted alkyl halide, suitably in an inert solvent such as dichloromethane or tetrahydrofuran and / or in the presence of a base such as triethylamine or pyridine at range from -60 to 30 ° C.

In the compound of formula (I), an appropriate group may optionally be liberated solvolytically or hydrogenolytically from the functionally modified amino and / or hydroxy group in a conventional manner. For example, a compound of formula I that contains a group of formula COOA can be converted to the corresponding compound of formula I, which instead contains COOH. For example, the groups of formula COOA may be saponified by treatment with sodium hydroxide or potassium hydroxide in water, a mixture of water and tetrahydrofuran, or a mixture of water and dioxane, at a temperature of from 0 to 100 ° C.

Reaction of the nitriles of formula I (e.g., nitriles in which R ² is cyano) with the nitric acid derivatives leads to the tetrazoles of formula I (e.g., compounds in which R ² is ΙΗ-5-tetrazolyl). Preferably, trialkyltin azides such as trimethyltin azide are used in an inert solvent such as an aromatic hydrocarbon such as toluene at a temperature in the range of from 20 to 150 ° C, preferably 80 to 140 ° C, or sodium azide in N-methylpyrrolidone at a temperature in the range of about 100 to about 200 ° C. Thereafter, the trialkyltin group is cleaved either by treatment with hydrochloric acid, for example dioxane, or with an alkali, for example ethanol and water, or with formic acid, for example methanol, or by chromatography on a silica gel column, for example ethyl acetate and methanol.

-7EN 283081 B6

The base of the formula I can be converted by treatment with an acid into the corresponding acid addition salt. For example, equivalent amounts of base and acid can be reacted in an inert solvent such as ethanol, after which the reaction mixture is evaporated. Suitable acids for this reaction are, in particular, those which give physiologically acceptable salts. Thus, inorganic acids such as sulfuric acid, nitric acid, hydrohalic acids such as hydrochloric acid or hydrobromic acid, phosphoric acids such as orthophosphoric acid, amidosulfonic acid, organic acids, especially aliphatic, alicyclic, araliphatic, aromatic or heterocyclic monofunctional acids can be used. or multifunctional carboxylic acids, sulfonic acids or acids derived from sulfuric acid such as formic acid, acetic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid , tartaric acid, malic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methane- or ethanesulfonic acid, ethanedisulfonic acid, ky selenium 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalene monosulfonic acid or naphthalenedisulfonic acid, and lauryl sulfuric acid. Salts with acids which are not physiologically harmless, for example picrates, can be used for the isolation and / or purification of the compounds of formula I.

On the other hand, compounds of the formula I which contain a carboxy or tetrazolyl group can be converted by treatment with bases (e.g. sodium or potassium hydroxide or carbonate) into the corresponding metal salts, in particular alkali or alkaline earth metals, or the corresponding ammonium salts. Potassium salts of tetrazolylderivatives are particularly preferred.

The compounds of formula I and their physiologically acceptable salts are also suitable for the manufacture of pharmaceutical preparations. In this manufacture, they are converted, together with at least one carrier or excipient and, if desired, together with one or more other active ingredients, into a suitable dosage form. The preparations thus obtained can be used as medicaments in human or veterinary medicine. Suitable carriers are organic or inorganic substances which are suitable for enteral (e.g. oral or rectal) or parenteral administration or for administration in the form of inhalation sprays and which do not react with the dream compounds. Specific examples of such materials include water, vegetable oils, benzyl alcohol, polyethylene glycols, glycerol triacetate and other fatty acid glycerides, gelatin, soybean lecithin, carbohydrates such as lactose or starch, magnesium stearate, talc and cellulose.

Tablets, coated tablets, capsules, syrups, juices or drops are particularly suitable for oral administration; Of particular interest are special coated tablets and capsules which contain coatings or capsule shells that resist gastric juices. For rectal administration, suppositories are used, for parenteral administration solutions, preferably oily or aqueous solutions, as well as suspensions, emulsions or implants. For application in the form of inhalation sprays, sprays containing the active ingredient either dissolved or suspended in a propellant gas mixture may be used. The active ingredient is advantageously used in micronized form and one or more physiologically acceptable solvents, for example ethanol, may be added. Inhalable solutions may be administered using conventional inhalers. The novel compounds can be lyophilized and the resulting lyophilizates used, for example, for the production of injectables. The above compositions may be sterilized and / or contain adjuvants such as preservatives, stabilizers and / or wetting agents, emulsifiers, salts for affecting the osmotic pressure, buffering agents, coloring agents and / or flavoring agents. If desired, these preparations may also contain one or more other active ingredients, for example one or more vitamins, diuretics and antifogistics.

-8EN 283081 B6

The compounds of the invention are generally administered in analogy to other known commercially available preparations, in particular analogously to those described in U.S. Pat. No. 4,880,804. Preferred dosages are in the range of about 1 mg to about 1 g, especially about 50 to about 1 mg. 500 mg, 5 per dosage unit. The daily dose is preferably in the range of about 0.1 to about 50 mg / kg, especially about 1 to about 10 mg / kg of body weight. The particular dose selected will depend on various factors for each individual patient, for example, the efficacy of the particular compound employed, the age, body weight, general health, sex and diet of the patient, the time and mode of administration and the rate of excretion, and the severity of the particular disease on which the treatment is directed. Oral administration is preferred.

The invention is illustrated by the following examples. These examples are illustrative only, and are not intended to limit the scope of the invention in any way. In the examples, the usual process is understood to mean the following procedure: if necessary, water is added to the reaction mixture, if necessary, the pH is adjusted to a value between 2 and 10, depending on the composition of the final product. It is extracted with ethyl acetate or dichloromethane, the organic phase is separated and dried over sodium sulphate and evaporated and the product is purified by silica gel chromatography and / or crystallization.

The term IP refers to imidazo [4,5-c] pyridine.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

A solution of 0.23 g of sodium in 20 ml of methanol is added dropwise over 15 minutes to a solution of 2.76 g of 30 2-butyl-5- (N, N-dimethylcarbamoylmethyl) -4,5-dihydro-4-oxo-3H-IP [which can be obtained by condensing valeric acid with 3,4-diamino-2-chloropyridine in the presence of polyphosphoric acid to give 2-butyl-4,5-dihydro-4-oxo-1- (or 3) H- IP], this compound is reacted with benzyl bromide in methanol in the presence of sodium methoxide to give 3-benzyl-2-butyl-4,5-dihydro-4-oxo-3H-IP, this compound is reacted with Ν, Ν-dimethylchloroacetamide in DMF 35 in the presence of potassium tert-butoxide to give 3-benzyl-2-butyl-5- (N, N-dimethylcarbamoylmethyl) -4,5-dihydro-4-oxo-3H-IP and cleavage from the product obtained by hydrogenolytic cleavage benzyl in 75 ml of methanol. The mixture was stirred at 20 ° C for 30 minutes and then evaporated. The residue was dissolved in 20 ml of dimethylformamide and a solution of 3.05 g of 4'-bromomethylbiphenyl-2-carboxylic acid methyl ester (IIa) in 10 ml of dimethylformamide was added dropwise at 0 ° C with stirring. The mixture was stirred at 20 ° C for 16 hours, evaporated and worked up in the usual manner. Chromatography on silica gel gave 2-butyl-5- (N, N-dimethylcarbamoylmethyl) -4,5-dihydro-3- (2'-methoxycarbonylbiphenylyl-4-methyl) -4-oxo-3H-IP.

b) A mixture of 1 g of the methyl ester obtained according to a), 12 ml of aqueous 2N sodium hydroxide solution 45 and 48 ml of methanol is boiled for 2 hours and then evaporated. The residue was worked up in the usual manner (using hydrochloric acid to adjust the pH to 3 and dichloromethane). 2-Butyl-5- (N, N-dimethylcarbamoylmethyl) -4,5-dihydro-3- (2'-carboxybiphenylyl-4-methyl) -4-oxo-3H-IP is obtained.

Example 2

Similar to Example 1, from 2.76 g of 2-butyl-4,5-dihydro-4-oxo-5- (N, N-dimethylcarbamoyl-9EN 283081 B6 methyl) -3H-IP and 2.98 g 178 DEG C., obtainable by condensation of p-tolylaldehyde with phenylacetonitrile in the presence of sodium ethoxide in ethanol, the resulting 2-phenyl-3-p-tolylacrylonitrile having a melting point of 61 DEG C. is brominated

N-bromosuccinimide in dichloromethane] gives 2-butyl-3- [p- (1-cyano-2-phenylvinyl) benzyl] -4,50-dihydro-4-oxo-5- (N, N-dimethylcarbamoylmethyl) -3H-IP.

Example 3

1.02 g valeric acid, 4.44 g 4-amino-1,2-dihydro-2-oxo-3- [2 '- (1H-5-tetrazolyl) biphenylyl-4-methylamino] -1- (N , N-dimethylcarbamoylmethyl) pyridine [obtainable by reacting 3-amino-4-benzylamino-1,2-dihydro-2-oxo-1- (N, N-dimethylcarbamoylmethyl) pyridine with 4-bromoethyl-2 4'-cyanobiphenyl to 4-benzylamino-3- (2'-cyanobiphenyl-4-methylamino) 1,2-dihydro-2-oxo-1- (N, N-dimethylcarbamoylmethyl) pyridine, which is reacted with trimethyltin azide, after formation of 4-benzylamino-1,2-dihydro-2-oxo-3- [2 '- (1H-5-tetrazolyl) biphenylyl-4-methylamino] -1- (N, N-dimethylcarbamoylmethyl) pyridine from which it is hydrogenolytically the benzyl group was cleaved] and 50 g of polyphosphoric acid were heated at 140 ° C for 5 hours. 4-Amino-1,2-dihydro-2-oxo-3- [N- (2 '- (1H-5-tetrazolyl) biphenylyl-4-methyl) -N-valerylamino] -1- (N, N-dimethylcarbamoylmethyl) pyridine and 1,2-dihydro-2-oxo-3- [2 '(1H-5-tetrazolyl) biphenylyl-4-methylamino) -1- (N, N-dimethylcarbamoylmethyl) -4-valerylaminopyridine. The mixture was cooled, poured onto ice and basified with sodium hydroxide. After usual work-up, 2-butyl-4,5-dihydro-5- (N, N-dimethylcarbamoylmethyl) -4-oxo-3- [2 '- (1H-5-tetrazolyl) biphenylyl-4-methyl] -3H-IP is obtained. mp 258 ° C.

Example 4

A mixture of 1.1 g of 3-p-aminobenzyl-2-butyl-4,5-dihydro-5- (N, N-dimethylcarbamoylmethyl) -4-oxo-3HIP [which can be obtained by reacting 2-butyl- 4,5-dihydro-5- (N, N-dimethylcarbamoylmethyl) -4-oxo-3H-IP with p-nitrobenzyl chloride to give 2-butyl-4,5-dihydro-5- (N, N-dimethylcarbamoylmethyl) - 3-p-nitrobenzyl-4-oxo-3H-IP was hydrogenated. 0.6 g phthalic anhydride and 40 ml trichloromethane were stirred at 20 ° C for 16 h. The precipitated 2-butyl-3- [4- (ocarboxybenzamido) benzyl] -4,5-dihydro-5- (N, N-dimethylcarbamoylmethyl) -4-oxo-3H-IP was filtered off.

Example 5

A mixture of 3.81 g of 3-p-aminobenzyl-2-butyl-4,5-dihydro-5- (N, N-dimethylcarbamoylmethyl) -4-oxo-3HIP, 3 ml of triethylamine, 0.5 g of 4-dimethylaminopyridine and 120 g. ml of dichloromethane was cooled to 5 ° C and treated dropwise with a solution of 2.88 g of o-trifluoromethanesulfonamidobenzoyl chloride in 20 ml of dichloromethane. The mixture was stirred at 20 ° C for 6 hours, evaporated and worked up in the usual manner. 2-Butyl-4,5-dihydro-5- (N, N-dimethylcarbamoylmethyl) -4-oxo-3- [4- (o-trifluoromethanesulfonamidobenzamido) benzyl] -3H-IP was obtained.

Example 6

A mixture of 4.10 g of 2-butyl-3-p-carboxybenzyl-4,5-dihydro-5- (N, N-dimethylcarbamoylmethyl) -4-oxo-3H-1P, 12 g of thionyl chloride and 35 ml of trichloromethane is boiled for 6 hours and then evaporate. The crude acid chloride obtained was freed from thionyl chloride residues several times in toluene and evaporated and then dissolved in 80 ml of tetrahydrofuran. The resulting solution was added dropwise to a solution of 1.7 g of anthranilic acid and 0.8 g of sodium hydroxide in 100 ml of water, stirred for 24 hours and acidified with hydrochloric acid to pH 5. After usual work-up, 2-butyl-3- [ p-10EN 283081 B6 (2-Carboxyanilino-carbonyl) benzyl] -4,5-dihydro-5- (Ν, Ν-dimethylcarbamoyl) methyl-4-oxo-3 H-IP.

Example 7

a) A solution of 3.1 g of 2-butyl-3- (2'-cyanobiphenylyl-4-methyl-4,5-dihydro-4-oxo-3H-IP [m.p. 2-Butyl-4,5-dihydro-4-oxo-1 (or 3) H-IP with 4'-bromomethyl-2-cyanobiphenyl in DMF in the presence of potassium carbonate] in 35 ml of dimethylformamide is mixed with 1 at 20 ° C with stirring. 25 g of potassium tert-butoxide After stirring for 45 minutes, a solution of 2.54 g of Ν, Ν-dimethylchloroacetamide in 25 ml of dimethylformamide is added dropwise and the mixture is stirred at 20 DEG C. for 16 hours and then worked up in the usual manner. butyl-3- (2'-cyanobiphenylyl-4-methyl) -4,5-dihydro-5- (N, N-dimethylcarbamoylmethyl) -4-oxo-3H-IP.

Analogously, the following 2-butyl-3- (2'-cyanobiphenyl-4-ylmethyl) -4,5-dihydro-4-oxo-5-R @ ³ -3H-IP:

with cinnamyl bromide:

-5-cinnamyl derivative [ie. 5- (3-phenyl-2-propen-1-yl) derivative], with 3-ethoxycarbonyl-2-phenyl-2-propen-1-yl bromide (ie, β-bromomethylcinnamate):

-5- (3-ethoxycarbonyl-2-phenyl-2-propen-1-yl) derivative, with α-bromophenylacetic acid methyl ester: -5- (α-methoxycarbonylbenzyl) derivative, with 2-methoxyimino-3,3 -dimethylbutylbromide: -5- (2-methoxyimino-3,3-dimethylbutyl) derivative, with 2-oxo-3-m-tolyl-5-oxazolinylmethylbromide: -5- (2-oxo-3-m) -tolyl-5-oxazolidinylmethyl) derivative, with bromoacetamide:

-5-carbamoyl methyl derivative, m.p. 219 ° C, with N-methylchloraceamide: -5- (N-methylcarbamoylmethyl) derivative, with N-ethylchloroacetamide:

-5- (N-ethylcarbamoylmethyl) derivative, with N-tert-butyl chloroacetamide:

-5- (N-tert-butylcarbamoylmethyl) -derivate, with N, N-diethylchloraceamide: -5- (N, N-diethylcarbamoylmethyl) derivative, with N, N-diisobutylchloroacetamide: -5- (N, N-diisobutylcarbamoylmethyl) derivative, m.p. 170 ° C, with N-phenylchloraceamide:

-5- (N-phenylcarbamoylmethyl) derivative, m.p. 107 ° C, with N-tolylchloraceamide: -5- (N-tolylcarbamoylmethyl) derivative, m.p. 175 ° C, with N-trifluoromethylphenylchloroacetamide: -5- ( N-Trifluoromethylphenylcarbamoylmethyl) derivative, with N-ethoxycarbonylphenyl chloroacetamide: -5- (N-ethoxycarbonylphenylcarbamoylmethyl) derivative, with N-chlorophenyl chloroacetamide: -5- (N-chlorophenylcarbamoylmethyl) -derivenyl, N- (2,6-dimethylacetamide) : -5- [N- (2,6-dimethylphenyl) carbamoylmethyl] derivative

With N- (2-pyridyl) chloroacetamide:

-5- [N- (2-pyridyl) carbamoylmethyl] derivative, with N-methyl-N-phenylchloracemide:

-5- (N-methyl-N-phenylcarbamoylmethyl) derivative, m.p. 106 DEG C., with N-methyl-N- (1,1-dimethyl-2-phenylethyl) chloroacetamide:

-5- [N-methyl-N- (1,1-dimethyl-2-phenylethyl) carbamoylmethyl] derivative, with N, N-diphenylchloroacetamide:

-5- (N, N-diphenylcarbamoylmethyl) derivative, with 3-chloropropionamide:

-5- (2-carbamoylethyl) derivative, with 3-chloro-N, N-dimethylpropionamide:

-5- (2-N, N-dimethylcarbamoylethyl) derivative, with 3-chloro-N-phenylpropionamide:

-5- (2-N-phenylcarbamoylethyl) derivative, with 3-chloro-N- (2,6-dimethylphenyl) propionamide:

-5- [2-N- (2,6-dimethylphenyl) carbamoylethyl] derivative, with 1-chloro-3-nitroacetone:

-5- (3-nitro-2-oxopropyl) derivative, with 6-BOC-amino-1-chloro-2-hexanone:

-5- (6-BOC-amino-2-oxohexyl) derivative, with N-ethoxycarbonylmethyl-N-methylacetic acid chloride: -5- (N-ethoxycarbonylmethyl-N-methylcarbamoylmethyl) derivative, with N- (methylsulfonyl) amide chloroacetic acids:

-5- (N-methylsulfonylcarbamoylmethyl) derivative, with N- (phenylsulfonyl) chloroacetic acid amide: -5- (N-phenylsulfonylcarbamoylmethyl) derivative, m.p. 193 ° C, with chloroacetic acid aziride:

-5-aziridinocarbonylmethyl derivative, with chloroacetic acid pyrrolidide:

-5-pyrrolidinocarbonylmethyl derivative, m.p. 166 ° C, with chloroacetic acid piperide:

-5-piperidinocarbonylmethyl derivative, with 2-oxopyrrolidide of chloroacetic acid: -5- (2-oxopyrrolidinocarbonylmethyl) derivative, with 2-oxopiperidide of chloroacetic acid:

-5- (2-oxopiperidinocarbonylmethyl) derivative, with chloroacetic acid 4-oxopiperidide:

-5- (4-oxopiperidinocarbonylmethyl) derivative, with 4-o-methoxyphenylpiperidine chloroacetic acid:

-5- (4-o-methoxyphenylpiperidinocarbonylmethyl) derivative, with chloroacetic acid 4- (2-thienyl) piperidine: -5- [4- (2-thienyl) piperidinocarbonylmethyl) derivative, with chloroacetic acid 4-p-methoxybenzoylpiperidide: - 5- (4-p-methoxybenzoylpiperidinocarbonylmethyl) derivative, with 2-ethoxycarbonylpyrrolidide chloroacetic acid:

-5- (2-ethoxycarbonylpyrrolidinocarbonylmethyl) derivative, with chloroacetic acid 3-ethoxycarbonylpiperidide: -5- (3-ethoxycarbonylpiperidinocarbonylmethyl) derivative, with chloroacetic acid 3-hydroxymethyl-4-p-chlorophenylpiperidide: -5- (3-hydroxymethyl) chloroacetic acid p-chlorophenylpiperidinocarbonylmethyl) derivative, with 3-N, N-diethylcarbamoylpiperidide:

-5- (3-N, N-diethylcarbamoylpiperidinocarbonylmethyl) derivative, m.p. 97 ° C, with 3-acetamidopyrrolidide chloroacetic acid:

- 12GB 283081 B6

-5- (3-acetamidopyrrolidinocarbonylmethyl) derivative, with chloroacetic acid morpholide: -5-morpholinocarbonylmethyl derivative, with 3-oxopiperazin chloroacetic acid: -5- (3-oxopiperazinocarbonylmethyl) derivative, with 4-methylpiperazo chloroacetic acid: -5 - (4-methylpiperazinocarbonylmethyl) derivative, with 4-o-methoxyphenylpiperazide chloroacetic acid: -5- (4-o-methoxyphenylpiperazinocarbonylmethyl) derivative, with 4-o-nitrophenylpiperazide chloroacetic acid: -5- (4-o-nitrophenylpiperazinocarbonylmethyl) , with chloroacetic acid 3-ethoxycarbonylpiperazide: -5- (3-ethoxycarbonylpiperazinocarbonylmethyl) derivative, with chloroacetic acid 4-BOC-piperazide: -5- (4-BOC-piperazinocarbonylmethyl) derivative, with chloroacetic acid 4- (2-pyrimidinyl) piperazide Acid: -5- [4- (2-pyrimidinyl) piperazinocarbonylmethyl] derivative, with 4-p-fluorophenylsulfonylpiperazide chloroacetic acid: -5- (4-p-fluorophenylsulfonylpiperazinocarbonylmethyl) derivative, m.p. 207 ° C, with methylthiomethyl chloride: -5-methylthiomethyl derivative, with methylsulfinylmethyl chloride:

-5-methylsulfinylmethyl derivative, with methylsulfonylmethyl chloride: -5-methylsulfonylmethyl derivative, with phenylthiomethyl chloride: -5-phenylthiomethyl derivative, m.p. 105 ° C, with phenylsulfinylmethylchoride: -5-phenylsulfinylmethyl derivative, mp 115 ° C , with phenylsulfonylmethyl bromide: -5-phenylsulfonylmethyl derivative, with 2-thienylthiomethyl chloride: -5- (2-thienylthiomethyl) derivative, with 2-pyridylaminosulfonylmethyl chloride: -5- (2-pyridylaminosulfonylmethyl) derivative, with methoxysulfonylmethyl chloride: -5- -derivative.

b) A mixture of 3.95 g of the compound obtained in a), 20.6 g of trimethyltin azide and 200 ml of toluene was boiled for 24 hours and then evaporated. The residue is taken up in 100 ml of methanolic hydrochloric acid, the mixture is stirred at 20 DEG C. for 2 hours and then worked up in the usual manner (using saturated sodium chloride solution and dichloromethane). Chromatography (using 80:20 ethyl acetate: hexane) afforded 2-butyl-4,5-dihydro-5- (N, N-dimethylcarbamoylmethyl) -4-oxo-3- [2 '- (1H-5)]. (tetrazolyl) biphenylyl-4-methyl] -3H-IP, m.p. The potassium salt monohydrate of this compound has a melting point of 296 ° C.

In a similar manner, the following 2-butyl-4,5-dihydro-4-oxo-3- [2 '- (1H-5-tetrazolyl) biphenylyl-4] was obtained from the 2'-cyanobiphenylyl compounds referred to in a). methyl] -5-R ³ -3HIP:

-5-cinnamyl derivative, m.p. 144 DEG C., -5- (3-ethoxycarbonyl-2-phenyl-2-propen-1-yl) derivative, m.p. 163 DEG C.,

- 13 GB 283081 B6

-5- (α-methoxycarbonylbenzyl) derivative, m.p. 208 ° C; -5- (2-methoxyimino-3,3-dimethylbutyl) derivative, m.p. 83 ° C; -5- (2-oxo-3- m-tolyl-5-oxazolidinylmethyl) derivative, m.p. 206 DEG C., -5-carbamoylmethyl derivative, m.p. 115 DEG-116 DEG C., -5- (N-methylcarbamoylmethyl) derivative, -5- (N-ethylcarbamoylmethyl) ) - derivative, -5- (N-tert-butylcarbamoylmethyl) - derivative whose tetrahydrate has a melting point of 212 ° C, -5- (N, N-diethylcarbamoylmethyl) derivative whose dihydrate has a melting point of 255 ° C, -5 - (N, N-diisobutylcarbamoylmethyl) derivative whose monohydrate has a melting point of 180 ° C, -5- (N-phenylcarbamoylmethyl) derivative whose monohydrate has a melting point of 227 ° C, -5- (No-tolylcarbamoylmethyl) derivative , m.p. 163 ° C, -5- (N-trifluoromethylphenylcarbamoylmethyl) derivative, -5- (N-ethoxycarbonylphenylcarbamoylmethyl) derivative, m.p. 190 ° C, -5- (N-chlorophenylcarbamoylmethyl) derivative, -5- [N- (2,6-dimethylphenyl) carbamoylmethyl] -d 247- C, -5- [N- (2-pyridyl) carbamoylmethyl] derivative, -5- (N-methyl-N-phenylcarbamoylmethyl) derivative, m.p. - [N-methyl-N- (1,1-dimethyl-2-phenylethyl) carbamoylmethyl] derivative, -5- (N, N-diphenylcarbamoylmethyl) derivative whose dihydrate has a melting point of 212 ° C, -5- ( 2-carbamoylethyl) derivative,

-5- (2-N, N-dimethylcarbamoylethyl) derivative, -5- (2-N-phenylcarbamoylethyl) derivative, -5- [2-N- (2,6-dimethylphenyl) carbamoylethyl] derivative, -5 - (3-nitro-2-oxopropyl) derivative,

-5- (6-BOC-amino-2-oxohexyl) -derivative, -5- (N-ethoxycarbonylmethyl-N-methylcarbamoylmethyl) derivative, -5- (N-methylsulfonylcarbamoylmethyl) derivative, -5- (N-phenylsulfonylcarbamoylmethyl) )-derivative,

-5-aziridinocarbonylmethyl derivative, -5-pyrrolidinocarbonylmethyl derivative, m.p. 215 DEG C., -5-piperidinocarbonylmethyl derivative,

-5- (2-oxopyrrolidinocarbonylmethyl) derivative, -5- (2-oxopiperidinocarbonylmethyl) derivative, -5- (4-oxopiperidinocarbonylmethyl) derivative, -5- (4-o-methoxyphenylpiperidinocarbonylmethyl) derivative, -5- [4] - (2-thienyl) piperidinocarbonylmethyl] derivative, -5- (4-p-methoxybenzoylpiperidinocarbonylmethyl) derivative, -5- (2-ethoxycarbonylpyrrolidinocarbonylmethyl) derivative, -5- (3-ethoxycarbonylpiperidinocarbonylmethyl) derivative, -5- (3-hydroxymethyl) 173 DEG C. -5- (3-acetamidopyrrolidinocarbonylmethyl) -5-morpholinocarbonylmethyl derivative, 4-p-chlorophenylpiperidinocarbonylmethyl) derivative, -5- (3-N, N-diethylcarbamoylpiperidinocarbonylmethyl) derivative,

-5- (3-oxopiperazinocarbonylmethyl) derivative, -5- (4-methylpiperazinocarbonylmethyl) derivative, -5- (4-o-methoxyphenylpiperazinocarbonylmethyl) derivative, -5- (4-o-nitrophenylpiperazinocarbonylmethyl) derivative, -5- ( 3-ethoxycarbonylpiperazinocarbonylmethyl) derivative, -5- (4-BOC-piperazinocarbonylmethyl) derivative, -5- [4- (2-pyrimidinyl) piperazinocarbonylmethyl) derivative, -5- (4-p-fluorophenylsulfonylpiperazinocarbonylmethyl) derivative, m.p. 248 ° C, -5-methylthiomethyl derivative, -5-methylsulfinylmethyl derivative,

- 14GB 283081 B6

-5-methylsulfonylmethyl derivative,

-5-phenylthiomethyl derivative,

-5-phenylsulfinylmethyl derivative,

-5-phenylsulfonylmethyl derivative,

-5- (2-thienyl) thiomethyl derivative,

-5- (2-pyridylaminosulfonylmethyl) derivative, -5-methoxysulfonylmethyl derivative.

Example 8

a) Similar to Example 7a) from 2-ethyl-3- (2'-cyanobiphenylyl-4-methyl) -4,5-dihydro-4-oxo-3HIP [m.p. 2-ethyl-4,5-dihydro-4-oxo-1 (or 3) H-IP with 4'-bromomethyl-2-cyanobiphenyl] and compounds of the general formula ER ³ as listed in Example 7b) yield the following 2 ethyl-3- (2'-cyanobiphenyl-4-ylmethyl) -4,5-dihydro-4-oxo-5-R @ ³ -3H-IP:

-5-c innamyl derivative,

-5- (3-ethoxycarbonyl-2-phenyl-2-propen-1-yl) derivative, -5- (α-methoxycarbonylbenzyl) derivative,

-5- (2-methoxyimino-3,3-dimethylbutyl) derivative, -5- (2-oxo-3-m-tolyl-5-oxazolidinylmethyl) derivative,

-5-carbamoylmethyl-derivative,

-5- (N-methylcarbamoylmethyl) derivative, -5- (N-ethylcarbamoylmethyl) derivative,

-5- (N-tert-butylcarbamoylmethyl) derivative

-5- (N, N-dimethylcarbamoylmethyl) derivative, m.p. 234 DEG C., -5- (N, N-diethylcarbamoylmethyl) derivative, m.p. 160 DEG C., -5- (N, N-diisobutylcarbamoylmethyl) derivative ,

-5- (N-phenylcarbamoylmethyl) derivative

-5- (N-o-tolylcarbamoylmethyl) derivative, -5- (N-o-trifluoromethylphenylcarbamoylmethyl) derivative, -5- (N-o-ethoxycarbonylphenylcarbamoylmethyl) derivative,

-5- (N-o-chlorophenylcarbamoylmethyl) derivative, -5- [N- (2,6-dimethylphenyl) carbamoylmethyl] derivative, -5- [N- (2-pyridyl) carbamoylmethyl] derivative,

-5- (N-methyl-N-phenylcarbamoylmethyl) derivative,

-5- [N-methyl-N- (1,1-dimethyl-2-phenylethyl) carbamoylmethyl] derivative, -5- (N, N-diphenylcarbamoylmethyl) derivative,

-5- (2-carbamoylethyl) derivative, -5- (2-N, N-dimethylcarbamoylethyl) derivative, -5- (2-N-phenylcarbamoylethyl) derivative, -5- [2-N- (2 6-dimethylphenyl) carbamoylethyl] derivative,

-5- (3-nitro-2-oxopropyl) derivative

-5- (6-BOC-amino-2-oxohexyl) derivative, -5- (N-ethoxycarbonylmethyl-N-methylcarbamoylmethyl) derivative, -5- (N-methylsulfonylcarbamoylmethyl) derivative,

-5- (N-phenylsulfonylcarbamoylmethyl) derivative.

-5-aziridinocarbonylmethyl derivative,

-5-pyrrolidinocarbonylmethyl derivative,

-5-piperidinocarbonylmethyl derivative, m.p. 221 DEG C., -5- (2-oxopyrrolidinocarbonylmethyl) derivative,

-5- (2-oxopiperidinocarbonylmethyl) derivative

- 15GB 283081 B6

-5- (4-oxopiperidinocarbonylmethyl) derivative, m.p. 189 ° C, -5- (4-o-methoxyphenylpiperidinocarbonylmethyl) derivative, m.p. 173 ° C, -5- [4- (2-thienyl) piperidinocarbonylmethyl] derivative -5- (4-p-methoxybenzoylpiperidinocarbonylmethyl) derivative, -5- (2-ethoxycarbonylpyrrolidinocarbonylmethyl) derivative, -5- (3-ethoxycarbonylpiperidinocarbonylmethyl) derivative, -5- (3-hydroxymethyl-4-p-chlorophenylpiperidinocarbonylmethyl) derivative -5- (3-N, N-diethylcarbamoylpiperidinocarbonylmethyl) derivative, -5- (3-acetamidopyrrolidinocarbonylmethyl) derivative, m.p. 153 ° C, -5-morpholinocarbonylmethyl derivative, m.p. 214 ° C, -5- (3 -oxopiperazinocarbonylmethyl) derivative, -5- (4-methylpiperazinocarbonylmethyl) derivative, -5- (4-o-methoxyphenylpiperazinocarbonylmethyl) melting point 156 ° C, -5- (4-o-nitrophenylpiperazinocarbonylmethyl) melting point 224 ° C, -5- (3-ethoxycarbonylpiperazinocarbonylmethyl) derivative, -5- (4-BOC-piperazinocarbonylmethyl) derivative, -5- [4- (2-pyrimidinyl) piperazinocarbonylmethyl] derivative, -5- (4-p-fluorophenylsulfonylpiperazinocarbonylmethyl) derivative, -5-methylthiomethyl derivative, -5-methylsulfinylmethyl derivative, -5-methylsulfonylmethyl derivative, - 5-phenylthiomethyl 1-derivative, -5-phenylsulfinylmethyl derivative, -5-phenylsulfonylmethyl derivative, m.p. 193 ° C, -5- (2-thienyl) thiomethyl derivative, -5- (2-pyridylaminosulfonylmethyl) derivative , -5-methoxysulfonylmethyl derivative.

b) Similar to Example 7b), the following 2-ethyl-4,5-dihydro-4-oxo-3- [2 '- (1 H) - was obtained from the 2'-cyanobiphenylyl compounds mentioned under a). -5-tetrazolyl) -biphenylyl-4-methyl] -5-R ³ -3H-IP:

-5-cinnamyl 1-derivative, -5- (3-ethoxycarbonyl-2-phenyl-2-propen-1-yl) derivative, -5- (α-methoxycarbonylbenzyl) derivative, -5- (2-methoxyimino- 3,3-dimethylbutyl) derivative, -5- (2-oxo-3-m-tolyl-5-oxazolidinylmethyl) derivative, -5-carbamoylmethyl derivative,

-5- (N-methylcarbamoylmethyl) derivative, -5- (N-ethylcarbamoylmethyl) derivative, -5- (N-tert-butylcarbamoylmethyl) derivative, -5- (N, N-dimethylcarbamoylmethyl) derivative, m.p. 182 ° C, -5- (N, N-diethylcarbamoylmethyl) derivative, m.p. 192 ° C, -5- (N, N-diisobutylcarbamoylmethyl) derivative, -5- (N-phenylcarbamoylmethyl) derivative,

-5- (N-tolylcarbamoylmethyl) derivative, -5- (N-trifluoromethylphenylcarbamoylmethyl) derivative, -5- (N-ethoxycarbonylphenylcarbamoylmethyl) derivative, -5- (N-chlorophenylcarbamoylmethyl) derivative, -5- [N- (2,6-dimethylphenyl) carbamoylmethyl] derivative, -5- [N- (2-pyridyl) carbamoylmethyl] derivative, -5- (N-methyl-N-phenylcarbamoylmethyl) derivative, -5- [N-methyl -N- (1,1-dimethyl-2-phenylethyl) carbamoylmethyl] derivative,

- 16GB 283081 B6

-5- (N, N-diphenylcarbamoylmethyl) derivative, -5- (2-carbamoylethyl) derivative, -5- (2-N, N-dimethylcarbamoylethyl) derivative, -5- (2-N-phenylcarbamoylethyl) - derivative, -5- [2-N- (2,6-dimethylphenyl) carbamoylethyl) derivative, -5- (3-nitro-2-oxopropyl) derivative, -5- (6-BOC-amino-2-oxohexyl) ) - derivative, -5- (N-ethoxycarbonylmethyl-N-methylcarbamoylmethyl) derivative, -5- (N-methylsulfonylcarbamoylmethyl) derivative, -5- (N-phenylsulfonylcarbamoylmethyl) derivative, -5-aziridinocarbonylmethyl derivative, -5 -pyrrolidinocarbonylmethyl derivative,

-5-piperidinocarbonylmethyl derivative, m.p. 200 ° C, -5- (2-oxopyrrolidinocarbonylmethyl) derivative, -5- (2-oxopiperidinocarbonylmethyl) derivative, -5- (4-oxopiperidinocarbonylmethyl) derivative, -5- ( 4-o-methoxyphenylpiperidinocarbonylmethyl) derivative, -5- [4- (2-thienyl) piperidinocarbonylmethyl] derivative, -5- (4-p-methoxybenzoylpiperidinocarbonylmethyl) derivative, -5- (2-ethoxycarbonylpyrrolidinocarbonylmethyl) derivative, -5- ( 3-ethoxycarbonylpiperidinocarbonylmethyl) derivative, -5- (3-hydroxymethyl-4-p-chlorophenylpiperidinocarbonylmethyl) derivative, -5- (3-N, N-diethylcarbamoylpiperidinocarbonylmethyl) derivative, -5- (3-acetamidopyrrolidinocarbonylmethyl) derivative 187 ° C, -5-morpholinocarbonylmethyl derivative, mp 196 ° C, -5- (3-oxopiperazinocarbonylmethyl) derivative, -5- (4-methylpiperazinocarbonylmethyl) derivative, -5- (4-o-methoxyphenylpiperazinocarbonylmethyl) mp 163 ° C, -5- (4-o-nitrophenylpiperazinocarbonylmethyl) mp 223 ° C -5- (3-ethoxycarbonylpiperazinocarbonylmethyl) derivative, -5- (4-BOC-piperazinocarbonylmethyl) derivative, -5- [4- (2-pyrimidinyl) piperazinocarbonylmethyl] derivative, -5- (4-p-fluorophenylsulfonylpiperazinocarbonylmethyl) - derivative, -5-methylthiomethyl derivative, -5-methylsulfinylmethyl derivative, -5-methylsulfonylmethyl derivative, -5-phenylthiomethyl derivative, -5-phenylsulfonylmethyl derivative, -5-phenylsulfonylmethyl derivative, m.p. 168 ° C, -5- (2-thienyl) thiomethyl derivative,

-5- (2-pyridylaminosulfonylmethyl) derivative, -5-methoxysulfonylmethyl derivative.

Example 9

a) Similar to Example 7a, starting from 2-cyclopropyl-3- (2'-cyanobiphenylyl-4-methyl) -4,5-dihydro-4-oxo-3H-IP [m.p. -cyclopropyl-4,5-dihydro-4-oxo-1 (or 3) H-IP with 4'-bromomethyl-2-cyanobiphenyl) and the compounds of formula ER ³ as shown in Example 7a, yield the following 2-cyclopropyl -3- (2'-Cyanobiphenylyl-4-methyl) -4,5-dihydro-4-oxo-5-R ³ -3H-IP:

-5-cinnamyl derivative, -5- (3-ethoxycarbonyl-2-phenyl-2-propen-1-yl) derivative,

- 17GB 283081 B6

-5- (α-methoxycarbonylbenzyl) derivative, -5- (2-methoxyimino-3,3-dimethylbutyl) derivative, -5- (2-oxo-3-m-tolyl-5-oxazolidinylmethyl) derivative, - 5-carbamoylmethyl derivative,

-5- (N-methylcarbamoylmethyl) derivative, -5- (N-ethylcarbamoylmethyl) derivative, -5- (N-tert-butylcarbnoylmethyl) derivative, -5- (N, N-dimethylcarbamoylmethyl) derivative, Rf = 0.16 (ethyl acetate / methanol, 9: 1), -5- (N, N-diethylcarbamoylmethyl) derivative, -5- (N, N-diisobutylcarbamoylmethyl) derivative, -5- (N-phenylcarbamoylmethyl) derivative, -5- (N-tolylcarbamoylmethyl) derivative, -5- (N-trifluoromethylphenylcarbamoylmethyl) derivative, -5- (N-ethoxycarbonylphenylcarbamoylmethyl) derivative, -5- (N-chlorophenylcarbamoylmethyl) derivative, -5- [N- (2,6-dimethylphenyl) carbamoylmethyl] derivative, -5- [N- (2-pyridyl) carbamoylmethyl] derivative, -5- (N-methyl-N-phenylcarbamoylmethyl) derivative,

-5- [N-methyl-N- (1,1-dimethyl-2-phenylethyl) carbamoylmethyl] derivative, -5- (N, N-diphenylcarbamoylmethyl) derivative, Rf = 0.39 (ethyl acetate / methanol, 9 : 1), -5- (2-carbamoylethyl) derivative,

-5- (2-N, N-dimethylcarbamoylethyl) derivative, -5- (2-N-phenylcarbamoylethyl) derivative, -5- [2-N- (2,6-dimethylphenyl) carbamoylethyl] derivative, -5 - (3-nitro-2-oxopropyl) derivative,

-5- (6-BOC-amino-2-oxohexyl) -derivative, -5- (N-ethoxycarbonylmethyl-N-methylcarbamoylmethyl) derivative, -5- (N-methylsulfonylcarbamoylmethyl) derivative, -5- (N-phenylsulfonylcarbamoylmethyl) ) - derivative, -5-aziridinocarbonylmethyl derivative,

-5-pyrrolidinocarbonylmethyl derivative, -5-piperidinocarbonylmethyl derivative, -5- (2-oxopyrrolidinocarbonylmethyl) derivative, -5- (2-oxopiperidinocarbonylmethyl) derivative, -5- (4-oxopiperidinocarbonylmethyl) derivative, -5- (4-o-methoxyphenylpiperidinocarbonylmethyl) derivative, -5- [4- (2-thienyl) piperidinocarbonylmethyl] derivative, -5- (4-p-methoxybenzoylpiperidinocarbonylmethyl) derivative, -5- (2-ethoxycarbonylpyrrolidinocarbonylmethyl) 1) difluctate, -5- (3-ethoxycarbonylpiperidinocarbonylmethyl) derivative, -5- (3-hydroxymethyl-4-p-chlorophenylpiperidinocarbonylmethyl) derivative, -5- (3-N, N-diethylcarbamoylpiperidinocarbonylmethyl) derivative, - 5- (3-acetamidopyrrolidinocarbonylmethyl) derivative, -5-morpholinocarbonylmethyl derivative, -5- (3-oxopiperazinocarbonylmethyl) derivative, -5- (4-methylpiperazinocarbonylmethyl) derivative, -5- (4-o-methoxyphenylpiperazinocarbonylmethyl) derivative -5- (4-o-nitrophenylpiperazinocarbonylmethyl) derivative, -5- (3-ethoxycarbonylpiperazinocarbonylmethyl) derivative, -5- (4-BOC-piperazinoka) rbonylmethyl) derivative, -5- [4- (2-pyrimidinyl) piperazinocarbonylmethyl] derivative, -5- (4-p-fluorophenylsulfonylpiperazinocarbonylmethyl) derivative, -5-methylthiomethyl derivative,

- 18GB 283081 B6

-5-methylsulfinylmethyl derivative,

-5-methylsulfonylmethyl derivative,

-5-phenylthiomethyl derivative,

-5-phenylsulfinylmethyl derivative,

-5-phenylsulfonylmethyl derivative,

-5- (2-thienyl) thiomethyl derivative,

-5- (2-pyridylaminosulfonylmethyl) derivative

-5-Methoxysulfonylmethyl derivative.

b) In a similar manner to Example 7b), the following 2-cyclopropyl-4,5-dihydro-4-oxo-3- [2 '- (1H-5) -isodium-2-cyclopropyl-4,5-dihydro-4-oxo-3- tetrazolyl) biphenyl-4-ylmethyl] -5-R @ ³ -3H-IP:

-5-innamy 1-derivative,

-5- (3-ethoxycarbonyl-2-phenyl-2-propen-1-yl) derivative, -5- (α-methoxycarbonylbenzyl) derivative,

-5- (2-methoxyimino-3,3-dimethylbutyl) derivative, -5- (2-oxo-3-m-tolyl-5-oxazolidinylmethyl) derivative,

-5-carbamoylmethyl derivative,

-5- (N-methylcarbamoylmethyl) derivative

-5- (N-ethylcarbamoylmethyl) derivative

-5- (N-tert-butylcarbamoyimethyl) derivative

-5- (N, N-dimethylcarbamoylmethyl) derivative, m.p. 231 ° C;

-5- (N, N-diethylcarbamoylmethyl) derivative, -5- (N, N-diisobutylcarbamoylmethyl) derivative,

-5- (N-phenylcarbamoylmethyl) derivative

-5- (N-tolylcarbamoylmethyl) derivative, -5- (N-trifluoromethylphenylcarbamoylmethyl) derivative, -5- (N-ethoxycarbonylphenylcarbamoylmethyl) derivative, -5- (N-chlorophenylcarbamoylmethyl) derivative, -5- [N- (2,6-dimethylphenyl) carbamoylmethyl] derivative, -5- [N- (2-pyridyl) carbamoylmethyl] derivative, -5- (N-methyl-N-phenylcarbamoylmethyl) derivative,

-5- (N-methyl-N- (1,1-dimethyl-2-phenylethyl) carbamoylmethyl) derivative, -5- (N, N-diphenylcarbamoylmethyl) derivative, m.p. 204 ° C, -5- (2- carbamoylethyl) derivative,

-5- (2-N, N-dimethylcarbamoylethyl) derivative,

-5- (2-N-phenylcarbamoylethyl) derivative, -5- [2-N- (2,6-dimethylphenyl) carbamoylethyl] derivative,

-5- (3-nitro-2-oxopropyl) derivative, -5- (6-BOC-amino-2-oxohexyl) derivative, -5- (N-ethoxycarbonylmethyl-N-methylcarbamoylmethyl) derivative, -5- (N-methylsulfonylcarbamoylmethyl) derivative, -5- (N-phenylsulfonylcarbamoylmethyl) derivative,

-5-aziridinocarbonylmethyl derivative,

-5-pyrrolidinocarbonylmethyl derivative,

-5-piperidinocarbonylmethyl derivative,

-5- (2-oxopyrrolidinocarbonylmethyl) derivative

-5- (2-oxopiperidinocarbonylmethyl) derivative

-5- (4-oxopiperidinocarbonylmethyl) derivative

-5- (4-o-methoxyphenylpiperidinocarbonylmethyl) derivative, -5- [4- (2-thienyl) piperidinocarbonylmethyl] derivative -5- (4-p-methoxybenzoylpiperidinocarbonylmethyl) derivative,

- 19GB 283081 B6

-5- (2-ethoxycarbonylpyrrolidinocarbonylmethyl) derivative,

-5- (3-ethoxycarbonylpiperidinocarbonylmethyl) derivative, -5- (3-hydroxymethyl-4-p-chlorophenylpiperidinocarbonylmethyl) derivative, -5- (3-N, N-diethylcarbamoylpiperidinocarbonylmethyl) derivative,

-5- (3-acetamidopyrrolidinocarbonylmethyl) derivative, -5-morpholinocarbonylmethyl derivative, -5- (3-oxopiperazinocarbonylmethyl) derivative, -5- (4-methylpiperazinocarbonylmethyl) derivative, -5- (4-o-methoxyphenylpiperazinocarbonylmethyl) derivative, o -5- (4-o-nitrophenylpiperazinocarbonylmethyl) derivative,

-5- (3-ethoxycarbonylpiperazinocarbonylmethyl) derivative, -5- (4-BOC-piperazinocarbonylmethyl) derivative, -5- [4- (2-pyrimidinyl) piperazinocarbonylmethyl] derivative, -5- (4-p-fluorophenylsulfonylpiperazinocarbonylmethyl) derivative ,

-5-methylthiomethyl derivative, -5-methylsulfinylmethyl derivative, -5-methylsulfonylmethyl derivative, -5-phenylthiomethyl derivative, -5-phenylsulfinylmethyl derivative,

-5-phenylsulfonylmethyl derivative, -5- (2-thienyl) thiomethyl derivative, -5- (2-pyridylaminosulfonylmethyl) derivative, -5-methoxysulfonylmethyl derivative.

Example 10

a) Similar to Example 7a) from 2-butyl-4,5-dihydro-4-oxo-3- [2 '- (2-triphenylmethyl-2H-5-tetrazolyl) biphenylyl-4-methyl] -3H-IP reaction with Ν, Ν-dimethylchloroacetamide gives 2-butyl-4,530 dihydro-5- (N, N-dimethylcarbamoylmethyl) -4-oxo-3- [2 '- (2-triphenylmethyl-2H-5-tetrazolyl) biphenylyl-4-methyl M.p. 187 ° C.

Similarly, the following 2-butyl-4,5-dihydro-4-oxo-3- [2 '- (2-triphenylmethyl-2H-5-tetrazolyl)] is obtained from compounds of formula ER ³ as shown in Example 7a). biphenylyl-435 methyl] -5-R @ ³ -3H-IP:

-5-cinnamyl derivative, m.p. 89 ° C;

-5- (3-ethoxycarbonyl-2-phenyl-2-propen-1-yl) derivative, m.p. 89 ° C, -5- (α-methoxycarbonylbenzyl) derivative, m.p. 94 ° C,

-5- (2-methoxyimino-3,3-dimethylbutyl) derivative, -5- (2-oxo-3-m-tolyl-5-oxazolidinylmethyl) derivative, m.p. 107 DEG C., -5-carbamoylmethyl derivative ,

-5- (N-methylcarbamoylmethyl) derivative

-5- (N-ethylcarbamoylmethyl) derivative

-5- (N-tert-butylcarbamoylmethyl) derivative

-5- (N, N-diethylcarbamoylmethyl) derivative, -5- (N, N-diisobutylcarbamoylmethyl) derivative,

-5- (N-phenylcarbamoylmethyl) derivative

-5- (N-o-tolylcarbamoylmethyl) derivative

-5- (N-trifluoromethylphenylcarbamoylmethyl) derivative, -5- (N-ethoxycarbonylphenylcarbamoylmethyl) derivative -5- (N, N-fluorophenylcarbamoylmethyl) -dirate, -5- [N- (2,6-dimethylphenyl) ) carbamoylmethyl] derivative

-20GB 283081 B6

-5- [N- (2-pyridyl) carbamoylmethyl] derivative

-5- (N-methyl-N-phenylcarbamoylmethyl) derivative

-5- [N-methyl-N- (1,1-dimethyl-2-phenylethyl) carbamoylmethyl] derivative,

-5- (N, N-diphenylcarbamoylmethyl) derivative

-5- (2-carbamoylethyl) derivative

-5- (2-N, N-dimethylcarbamoylethyl) derivative,

-5- (2-N-phenylcarbamoylethyl) derivative,

-5- [2-N- (2,6-dimethylphenyl) carbamoylethyl] derivative,

-5- (3-nitro-2-oxopropyl) derivative,

-5- (6-BOC-amino-2-oxohexyl) derivative, -5- (N-ethoxycarbonylmethyl-N-methylcarbamoylmethyl) derivative, -5- (N-methylsulfonylcarbamoylmethyl) derivative,

-5- (N-phenylsulfonylcarbamoylmethyl) derivative

-5-aziridinocarbonylmethyl derivative,

-5-pyrrolidinocarbonylmethyl derivative,

-5-piperidinocarbonylmethyl derivative,

-5- (2-oxopyrrolidinocarbonylmethyl) derivative

-5- (2-oxopiperidinocarbonylmethyl) derivative

-5- (4-oxopiperidinocarbonylmethyl) derivative

-5- (4-o-methoxyphenylpiperidinocarbonylmethyl) derivative,

-5- [4- (2-thienyl) piperidinocarbonylmethyl] derivative,

-5- (4-p-methoxybenzoylpiperidinocarbonylmethyl) derivative,

-5- (2-ethoxycarbonylpyrrolidinocarbonylmethyl) derivative,

-5- (3-ethoxycarbonylpiperidinocarbonylmethyl) derivative,

-5- (3-hydroxymethyl-4-p-chlorophenylpiperidinocarbonylmethyl) derivative,

-5- (3-N, N-diethylcarbamoylpiperidinocarbonylmethyl) derivative, -5- (3-acetamidopyrrolidinocarbonylmethyl) derivative,

-5-morpholinocarbonylmethyl derivative,

-5- (3-oxopiperazinocarbonylmethyl) derivative

-5- (4-methylpiperazinocarbonylmethyl) derivative

-5- (4-o-methoxyphenylpiperazinocarbonylmethyl) derivative,

-5- (4-o-nitrophenylpiperazinocarbonylmethyl) derivative,

-5- (3-ethoxycarbonylpiperazinocarbonylmethyl) derivative,

-5- (4-BOC-piperazinocarbonylmethyl) derivative, -5- [4- (2-pyrimidinyl) piperazinocarbonylmethyl] derivative, -5- (4-p-fluorophenylsulfonylpiperazinocarbonylmethyl) derivative,

-5-methylthiomethyl derivative,

-5-methylsulfinylmethyl derivative,

-5-methylsulfonylmethyl derivative,

-5-phenylthiomethyl derivative,

-5-phenylsulfinylmethyl derivative,

-5-phenylsulfonylmethyl derivative,

-5- (2-thienyl) thiomethyl derivative,

-5- (2-pyridylaminosulfonylmethyl) derivative

-5-Methoxysulfonylmethyl derivative as well as the following 2-ethyl-4,5-dihydro-4-oxo-3- [2 '- (2-triphenylmethyl-2H-5-tetrazolyl) biphenylyl-4-methyl] -5-R ^3- H-IP:

-5-cinnamyl derivative,

-5- (3-ethoxycarbonyl-2-phenyl-2-propen-1-yl) derivative,

-5- (α-methoxycarbonylbenzyl) derivative

-5- (2-methoxyimino-3,3-dimethylbutyl) derivative,

-21 GB 283081 B6

-5- (2-oxo-3-m-tolyl-5-oxazolidinylmethyl) derivative, -5-carbamoylmethyl derivative, -5- (N-methylcarbamoylmethyl) derivative, -5- (N-ethylcarbamoylmethyl) derivative, -5- (N-tert-butylcarbamoylmethyl) derivative, -5- (N, N-dimethylcarbamoylmethyl) derivative, -5- (N, N-diethylcarbamoylmethyl) derivative, -5- (N, N-diisobutylcarbamoylmethyl) - derivative, -5- (N-phenylcarbamoylmethyl) derivative, -5- (N-tolylcarbamoylmethyl) derivative, -5- (N-trifluoromethylphenylcarbamoylmethyl) derivative, -5- (N-ethoxycarbonylphenylcarbamoylmethyl) derivative, -5- ( N-chlorophenylcarbamoylmethyl) derivative, -5- [N- (2,6-dimethylphenyl) carbamoylmethyl] derivative, -5- [N- (2-pyridyl) carbamoylmethyl] derivative, -5- (N-methyl-N) -phenylcarbamoylmethyl) derivative, -5- [N-methyl-N- (1,1-dimethyl-1-2-phenyl) carbamoylmethyl) derivative, -5- (N, N-diphenylcarbamoylmethyl) derivative, -5- (2-carbamoylethyl) derivative, -5- (2-N, N-dimethylcarbamoylethyl) derivative, -5- (2-N-phenylcarbamoylethyl) derivative, -5- [2-N- (2,6-dimethylphenyl) (carbamoylethyl) derivative, -5- (3-nit r-2-oxopropyl) derivative, -5- (6-BOC-amino-2-oxohexyl) derivative, -5- (N-ethoxycarbonylmethyl-N-methylcarbamoylmethyl) derivative, -5- (N-methylsulfonylcarbamoylmethyl) - derivative, -5- (N-phenylsulfonylcarbamoylmethyl) derivative, -5-aziridinocarbonylmethyl derivative, -5-pyrrolidinocarbonylmethyl derivative, -5-piperidinocarbonylmethyl derivative, -5- (2-oxopyrrolidinocarbonylmethyl) derivative, -5- (2 -oxopiperidinocarbonylmethyl) derivative, -5- (4-oxopiperidinocarbonylmethyl) derivative, -5- (4-o-methoxyphenylpiperidinocarbonylmethyl) derivative, -5- [4- (2-thienyl) piperidinocarbonylmethyl] derivative, -5- (4 -p-methoxybenzoylpiperidinocarbonylmethyl) derivative, -5- (2-ethoxycarbonylpyrrolidinocarbonylmethyl) derivative, -5- (3-ethoxycarbonylpiperidinocarbonylmethyl) derivative, -5- (3-hydroxymethyl-4-p-chlorophenylpiperidinocarbonylmethyl) derivative, -5- (3- N, N-diethylcarbamoylpiperidinocarbonylmethyl) derivative, -5- (3-acetamidopyrrolidinocarbonylmethyl) derivative, -5-morpholinocarbonylmethyl derivative, -5- (3-oxopiperazinocarbonylmethyl) - derivative, -5- (4-methylpiperazinocarbonylmethyl) derivative, -5- (4-o-methoxyphenylpiperazinocarbonylmethyl) derivative, -5- (4-o-nitrophenylpiperazinocarbonylmethyl) derivative, -5- (3-ethoxycarbonylpiperazinocarbonylmethyl) derivative, -5 - (4-BOC-piperazinocarbonylmethyl) derivative, -5- [4- (2-pyrimidinyl) piperazinocarbonylmethyl] derivative, -5- (4-p-fluorophenylsulfonylpiperazinocarbonylmethyl) derivative, -5-methylthiomethyl derivative, -5-methylsulfinylmethyl - derivative, -5-methylsulfonylmethyl derivative,

-5-phenylthiomethyl derivative,

-22EN 283081 B6

-5-phenylsulphines of methyl 1-derivative,

-5-phenylsulfonylmethyl derivative, -5- (2-thienyl) thiomethyl derivative, -5- (2-pyridylaminosulfonylmethyl) derivative, -5-methoxysulfonylmethyl derivative.

(b) The product obtained in (a) (1 g) was dissolved in 60 ml of 4N hydrochloric acid in dioxane and stirred at 20 ° C for 16 hours. The solution was evaporated and worked up in the usual manner. 2-Butyl-4,5-dihydro-5- (N, N-dimethylcarbamoylmethyl) -4-oxo-3- [2 '- (1H-5-tetrazolyl) biphenylyl-4-methyl] -3H-IP was obtained. mp 258 ° C.

Similarly, the corresponding 2-triphenylmethyl-2H-5-tetrazolyl compounds mentioned in a) yield the ΙΗ-5-tetrazolyl compounds shown in Examples 7b) and 8b).

Example 11

Similar to Example 7a), by reaction of 2-butyl-3- (p-2-cyano-2-phenylvinylbenzyl) -4,5-dihydro-4-oxo-3H-IP [m.p. 2-butyl-4,5-dihydro-4-oxo-1 (or 3) H-IP and 3-p-bromomethylphenyl-2-phenyl acrylonitrile] with Ν, Ν-dimethylchloroacetamide afford 2-butyl-3- (β 2 -cyano) -2-phenylvinylbenzyl) -4,5-dihydro-5- (N, N-dimethylcarbamoylmethyl) -4-oxo-3H-IP.

Example 12

To a solution of 0.44 g of 2-butyl-3- (2'-cyanobiphenylyl-4-methyl) -4,5-dihydro-4-oxo-3H-IP-5-acetic acid [B; m.p. 222 DEG C., obtainable by reaction of 2-butyl-3- (2'-cyanobiphenylyl-4-methyl) 4,5-dihydro-4-oxo-3H-IP with ethyl bromoacetate to give the 5-ethoxycarbonylmethyl derivative m.p. 152 DEG C., then saponified] in 14 ml of tetrahydrofuran, 210 mg of DCCI are added, the mixture is stirred at 20 DEG C. for 10 minutes, 72 mg of pyrrolidine are added, and the mixture is stirred at 20 DEG C. for a further 18 hours. Then the mixture is filtered, the filtrate is worked up in the usual manner and the crude product is chromatographed on silica gel (using a mixture of ethyl acetate and methanol 80:20). There was obtained 2-butyl-3- (2'-cyanobiphenylyl-4-methyl) -4,5-dihydro-4-oxo-5-pyrrolidinocarbonylmethyl-1H-IP, m.p. 166 ° C.

Example 13

To a solution of 4.4 g of B and 2.44 g of 1-p-fluorophenylsulfonylpiperazine in 90 ml of DMF was added 1.94 g of DAPECI, 1.36 g of 1-hydroxybenzotriazole and 1.1 ml of N-methylmorpholine in succession. Stir 5 hours at 20 ° C. The product is precipitated with water, filtered, washed with water and dried. There was obtained 2-butyl-3- (2'-cyanobiphenylyl-4-methyl) -4,5-dihydro-4-oxo-5- (4-fluorophenylsulfonylpiperazino) carbonylmethyl-1-3 H-IP, m.p. 207 ° C.

Example 14

A solution of 4.4 g of compound B in 20 ml of tetrahydrofuran was added dropwise with stirring to a solution of 1.6 g of 1,1'-carbonyldiimidazole in 20 ml of tetrahydrofuran and the mixture was heated for 30 minutes. After cooling, 1.6 g of benzenesulfonamide is added, the mixture is stirred for 10 minutes, a solution of 1.48 g of 1,8-diazabicyclo [5.4.0] undec-7-ene in 10 ml of tetrahydrofuran is added dropwise, and the mixture is stirred for 18 hours. The mixture was stirred at 20 ° C and then worked up in the usual manner (using 1N hydrochloric acid and dichloromethane). There was obtained 2-butyl-3- (2'-cyanobiphenylyl-4-methyl) -4,5-dihydro-4-oxo-5- (N-phenylsulfonylcarbamoylmethyl) -3H-IP, m.p. 193 ° C.

-23 GB 283081 B6

Example 15

Similar to Example 12, reaction of 2-ethyl-3- (2'-cyanobiphenylyl-4-methyl) -4,5-dihydro-4-oxo-3H-IP-5-acetic acid [m.p. obtained by reacting 2-ethyl-3- (2'-cyanobiphenylyl-4-methyl) -4,5-dihydro-4-oxo-3H-IP with ethyl bromoacetate, then from the obtained 2-ethyl-3- (2'- 143 ° C releases the desired product by saponification] with diethylamine in the presence of DCCI affords 2-ethyl-3- (2'-cyanbiphenylyl) cyanobiphenylyl-4-methyl) -4,5-dihydro-4-oxo-5-ethoxycarbonylmethyl 4-methyl) -4,5-dihydro-4-oxo-5- (N, N-diethylcarbamoylmethyl) -3H-IP, m.p. 160 ° C.

Example 16

Similar to Example 1b) by saponification of the ethyl esters of Example 7b), the following 2-butyl-4,5-dihydro-4-oxo-3- [2 '- (1H-5-tetrazolyl) biphenylyl-4-methyl] was obtained ] -5-R ³ -3 H-IP:

-5- (3-carboxy-2-phenyl-2-propen-1-yl) derivative and -5- (N-o-carboxyphenylcarbamoylmethyl) derivative.

Example 17

A solution of 1 g of 2-butyl-4,5-dihydro-5- (3-nitro-2-oxopropyl) -4-oxo-3- [2 '- (1H-5-tetrazolyl) biphenyl-4-methyl] -3H-IP in 20 ml of methanol was hydrogenated to 0.3 g of 5% palladium on carbon at 20 ° C and under normal pressure until the calculated amount of hydrogen was consumed. The catalyst was filtered off and the mixture was evaporated. 5- (3-Amino-2-oxopropyl) -2-butyl-4,5-dihydro-4-oxo-3- [2 '- (1H-5-tetrazolyl) biphenylyl-4-methyl] -3H-IP was obtained.

Example 18

A solution of 1 g of 5- (6-BOC-amino-2-oxohexyl) -2-butyl-4,5-dihydro-4-oxo-3- [2 '- (1H-5-tetrazolyl) biphenylyl-4-methyl) The -3 H-IP in 20 mL of dichloromethane and 20 mL of trifluoroacetic acid was stirred at 20 ° C for 1 hour, then the mixture was evaporated and worked up in the usual manner. 5- (6-amino-2-oxohexyl) -2-butyl-4,5-dihydro-4-oxo-3- [2 '- (1H-5-tetrazolyl) biphenylyl-4-methyl] -3H-IP was obtained.

Similarly, from 2-ethyl- or 2-butyl-4,5-dihydro-4-oxo-3- [2 '- (1H-5-tetrazolyl) biphenyl-4-methyl] 5- (4-BOC-piperazinocarbonylmethyl) -3H-IP affords 2-ethyl or 2-butyl-4,5-dihydro-4-oxo-3- [2 '(1H-5-tetrazolyl) biphenylyl-4-methyl] -5- (4-piperazinocarbonylmethyl) - 3H-IP.

Example 19

A mixture of 7.67 g of 2-butyl-4,5-dihydro-5- (3,3-dimethyl-2-oxobutyl) -3- [2 '- (2-triphenylmethyl-2H-5-tetrazolyl) biphenylyl-4-methyl] -3H-IP, 1.67 g of O-methylhydroxylamine hydrochloride, 200 ml of methanol and 3.2 g of pyridine were stirred at 20 ° C for 72 hours. Intermediate yields 2-butyl-4,5-dihydro-5- (3,3-dimethyl-2-oxobutyl) -3- [2 '- (1H-5-tetrazolyl) biphenylyl-4-methyl] -3H-IP, which is not insulated. After usual work-up (chromatography on silica gel with a mixture of ethyl acetate and methanol), 2-butyl-4,5-dihydro-5- (3,3-dimethyl-2-methoxyiminobutyl) -3- [2 '- (1H-5-tetrazolyl) is obtained. (biphenylyl-4-methyl) -3H-IP, m.p. 83 ° C.

The following examples relate to pharmaceutical preparations which contain the active compounds of the formula I or their salts.

CZ 283081 B6

Example A

Tablets and dragees

Tablets of the following composition are optionally compressed by compression, optionally coated with a conventional coating for sucrose dragees:

active ingredient of the formula I microcrystalline cellulose lactose maize starch magnesium stearate fine - grained silica 100 mg 278.8 mg 110 mg 11 mg 5 mg 0.2 mg

Example B

Hard gelatine capsules

Usual two-piece hard gelatine capsules are filled with a mixture of the following composition (one capsule fill composition):

active ingredient of the formula I lactose cellulose magnesium stearate 100 mg 150 mg 50 mg 6 mg

Example C

Soft gelatin capsules

Typical soft gelatin capsules are filled with a mixture of 50 mg of active ingredient and 250 mg of olive oil.

Example D

Injection

A solution of 200 g of active ingredient in 2 kg of 1,2-propanediol is made up to 10 l with water and then filled with an injection so that each injection contains 20 mg of active ingredient.

Example E

Aqueous suspension for oral administration

An aqueous suspension of the active ingredient is prepared in a conventional manner. The unit dose (5 ml) contains 100 mg of active ingredient, 100 mg of carboxymethylcellulose sodium, 5 mg of sodium benzoate and 100 mg of sorbitol.

Pharmacological testing report

Binding of angiotensin II to rat adrenal cortical microsomes was determined by a method analogous to that described by AT Chiu et al., J. Pharmacol. Exp. Therap. 5,250,867-874 (1989). IC 50 values [nmol x Γ ¹ ] were determined for some typical compounds of formula I

(AND)

Example number Melting point (° C) R ¹ R ² R ³ IC 50 (nmol x ^-1 ) 9b 231 Cyp Tet -CH ₂ -CO-NMe ₂ 0.6 7b 255 Bu Tet -CH ₂ -CO-NEt ₂ 0.6 8b 192 Et Tet -CH ₂ -CO-NEt ₂ 0.7 8b 200 Et Tet -CH ₂ -CO-piperidino 0.7 7b 215 Bu Tet -CH ₂ -CO-pyrrolidino 1.1 7b 258 Bu Tet -CH ₂ -CO-NMe ₂ 1.6 7b 163 Bu Tet -CH ₂ -CO-NH- (o-tolyl) 2.1 7b 171 Bu Tet -CH ₂ -CO-N (Me) -Ph 2.2 7b 173 Bu Tet -CH ₂ -CO- (3-N, N-diethylcarbamoylpiperidino) 2.3 8b 187 Et Tet -CH ₂ -CO- (3-acetamidopyrrolidino) 1.7 8b 196 Et Tet -CH ₂ -CO-morpholino 1.7 8b 163 Et Tet -CH ₂ -CO- (4-Methoxyphenylpiperazino) 3.4 7b 180 Bu Tet -CH ₂ -CO-N (iBu) ₂ 3.5 7b 212 Bu Tet -CH ₂ -CO-NH-tBu 3.8 7b 208 Bu Tet -CH (Ph) -COOMe 4.0 8b 168 Et Tet -CH ₂ -SO ₂ -Ph 4.8 9b 204 Cyp Tet -CH ₂ -CO-NPh ₂ 5.7 7b 206 Bu Tet -CH ₂ - (2-oxo-3-m-tolyl-oxazolidin-5-yl) 5.8 7b 227 Bu Tet -CH ₂ -CO-NH-Ph 6.0 8b 223 Et Tet -CH ₂ -CO- (4-o-nitrophenylpiperazino) 7.5 7b 247 Bu Tet -CH ₂ -CO-NH- (2,6-dimethylphenyl) 7.9 7b 144 Bu Tet -CH, -CH = CH-Ph 8.5 7b 163 Bu Tet -CH ₂ -CPh = CH-COOEt 8.9 7b 212 Bu Tet -CH ₂ -CO-NPh ₂ 15 Dec 7b 190 Bu Tet -CH ₂ -CO-NH- (o-ethoxycarbonylphenyl) 16

-26GB 283081 B6

Example number Melting point (° C) R ¹ R ² R ³ IC 50 (nmol x ^-1 ) 7b 248 Bu Tet -CH ₂ -CO- (4-p-fluorophenylsulfonylpiperazino) 16.5 7a 115 Bu CN -CH ₂ -SO-Ph 41 7a 105 Bu CN -CH ₂ -S-Ph 54

Bu = butyl, tBu = tert-butyl, Cyp = cyclopropyl, Et = ethyl, iBu = isobutyl, iPr = isopropyl, Me = methyl, Ph = phenyl, Pr = propyl and Tet = ΙΗ-5-tetrazolyl

Claims (11)

An imidazopyridine derivative of the general formula I (I), wherein: R is a radical of formula R ¹ is A or cyclopropyl R ² represents cyano or ΙΗ 5-tetrazolyl, R ³ is C 2 -C 6 alkenyl which is once substituted with Ar, or -CH ₂ -R ⁹ or -CHR ¹⁰ Ar, R ⁶ and R ⁷ are each hydrogen, A, Ar or ArCH ₂ -, or R ⁶ and R ⁷ taken together represent an alkylene chain of 4 to 5 carbon atoms optionally substituted once with -CO-N (A) ₂ and / or -NH-CO-A and / or interrupted by an oxygen atom or -NR ¹⁶ -, R ⁹ is -C (= N-OA) -A, Het ¹ , -CO-NR ⁶ R ⁷ or -S (O) _m -Ar, -27GB 283081 B6 R10 represents a carboxy group or a group of formula COOA, R ¹⁶ represents a group of formula Ar, COOA or SO ₂ -Ar, AND C 1 -C 6 alkyl Ar represents unsubstituted phenyl or phenyl which is once substituted by A, OA, COOA, NO ₂ or Hal, Het ¹ is 2-oxo-3-Ar-5-oxazolinyl; Hal represents a fluorine, chlorine, bromine or iodine atom, and m is 0, 1 or 2 and salts thereof. A compound according to claim 1, wherein: R is a radical of formula R ¹ represents A, R ² is CN or 1H-5-tetrazolyl, R ³ is C 2 -C 6 alkenyl, which is once substituted with Ar, or -CH 2 -R ⁹ , R ⁶ and R ⁷ are each hydrogen, A, Ar or ArCH ₂ -, R ⁹ is -C (= N-OA) -A, Het ¹ , or -CO-NR ⁶ R ⁷ , R ¹⁰ represents a carboxy group or a group of formula COOA, A is C 1 -C 6 alkyl, Ar is unsubstituted phenyl or phenyl substituted once with A, OA, COOA, NO ₂ or Hal, Het ¹ is 2-oxo-3-Ar-5-oxazolidinyl, Hal represents a fluorine, chlorine, bromine or iodine atom, and m represents 0, 1 or 2, and salts thereof. The imidazopyridine derivatives of the formula I according to claim 2 which are (a) 2-butyl-5-cinnamyl-4,5-dihydro-4-oxo-3- [2 '- (1H-5-tetrazolyl) biphenylyl-4-methyl] -3Himidazo [4,5-c] pyridine; b) 2-butyl-4,5-dihydro-5- (N, N-dimethylcarbamoyl methyl) -4-oxo-3- [2 '- (1H-5-tetrazolyl) biphenylyl-4-methyl] -3H- imidazo [4,5-c] pyridine; c) 2-butyl-4,5-dihydro-5-a-methoxycarbonylbenzyl-4-oxo-3- [2 '- (1H-5-tetrazolyl) biphenylyl-4-methyl] -3H-imidazo [4,5-c] pyridine; d) 2-Butyl-4,5-dihydro-5- (2-methoxyimino-3,3-dimethylbutyl-4-oxo-3- [2 '- (1H-5-tetrazolyl) biphenylyl-4-methyl] -3H -imidazo [4,5-c] pyridine; e) 2-Butyl-4,5-dihydro-4-oxo-5- (2-oxo-3-m-tolyl-5-oxazolidinylmethyl) -3- [2 '- (1H-5-tetrazolyl) biphenylyl-4-methyl 3 H -imidazo [4,5- c] pyridine. 4. A process for the preparation of imidazopyridine derivatives of the formula I as claimed in claim 1 and salts thereof, characterized in that a) a compound of formula II E — CH · (Π), where it represents a chlorine, bromine or iodine atom, or a free or reactive functionally modified hydroxy group, and as defined above, is reacted with a compound of formula III H-R (III), wherein R is as defined above, or is b) a compound of formula IV -29EN 283081 B6 (IV), where R ¹⁷ represents a group of the formula R'-CO or hydrogen, and R ¹⁸ represents a hydrogen atom when R ¹⁷ represents a group of formula R 1 -CO, or a group of formula R 1 -CO 2 ^; -CO when R ¹⁷ represents a hydrogen atom, and R ¹ , R ² and R ³ are as defined above, heated in polyphosphoric acid, acetic acid or diglyme to a temperature in the range of 80 to 180 ° C, or c) a compound of formula VII (VII), wherein R ¹ and R ² are as defined above, is reacted with a compound of formula VIII ER ³ (VIII), where R ³ and E are as defined above, or are -30GB 283081 B6 d) for the preparation of a compound wherein R ³ represents a group of the formula CH 2 -CO-NR ⁶ R ⁷ , a carboxylic acid corresponding to the general formula I reacts but instead of the radical R ³ contains a group of the formula -CH 2 -COOH or one of its functional derivatives , with a compound of the formula HNR ⁶ R ⁷ , or with e) a compound of formula I is freed from one of its functional derivatives by treatment with a solvolyzing or hydrogenolyzing agent, and / or in a compound of formula Ijeden or more radicals R and / or R ² is converted to one or more other radicals R and / or R ² and or the base or acid of the formula I is converted into one of its salts. Process according to claim 4 for the preparation of imidazopyridine derivatives according to claim 2, characterized in that the corresponding starting materials are used to obtain the abovementioned derivatives. Pharmaceutical preparation for the treatment of angiotensin II-dependent diseases, characterized in that it comprises at least one imidazopyridine derivative of the formula I according to claim 1 and / or a physiologically acceptable acid addition salt thereof. Pharmaceutical preparation according to claim 6, characterized in that it comprises at least one imidazopyridine derivative of the general formula I according to claim 2 and / or a physiologically acceptable acid addition salt thereof. The imidazopyridine derivatives of the formula I according to claim 1 and their physiologically acceptable acid addition salts for use as medicaments. The imidazopyridine derivatives of the formula I according to claim 2 and their physiologically acceptable acid addition salts for use as medicaments. The imidazopyridine derivatives of the general formula I according to claim 1 and / or their physiologically acceptable acid addition salts for the manufacture of medicaments for the treatment of angiotensin II dependent diseases. The imidazopyridine derivatives of the general formula I according to claim 2 and / or their physiologically acceptable acid addition salts for the manufacture of medicaments for the treatment of angiotensin II dependent diseases.